We aim to develop novel non-invasive and reiterative tests of nerve (small) fibre damage and repair in human diabetic neuropathy. We will quantify corneal nerve fibre degeneration and regeneration in diabetic patients compared with control subjects. We will assess circulating levels of the neurotrophin receptor p75 (p75NTR) as an index of small fibre stress/damage. Both measures will be validated against gold standard measures of neuropathic severity. A cross-sectional study will assess corneal nerve morphology and the p75NTR titre in diabetic subjects with a varying severity of neuropathy and non-diabetic control subjects. Moreover, subjects who have either recently undergone or are planned to undergo fascicular sural nerve biopsy will also have assessment of corneal nerve morphology and the p75NTR titre to define their exact relationship with peripheral nerve fibre degeneration and regeneration. Corneal nerve morphology and the p75NTR titre will be assessed in Type 1 diabetic subjects with painful neuropathy in a trial of strict glycaemic control using continuous subcutaneous insulin infusion, in order to assess the effect of near-normoglycemia and reduced glucose flux on these parameters. To further understand the relevant biology of the p75mR, and place its clinical assessment into a scientific frame of reference, we will undertake in vitro and animal studies. Tissue culture studies of neurones and Schwann cells will be employed to assess the effects of hyperglycemia, oxidative stress and NGF deficiency on expression, turnover and shedding of p75NTR. The role of these regulators specifically NGF therapy will be assessed longitudinally in STZ-rats in both peripheral nerve and in sensory ganglia to help further refine our understanding of the site of expression and shedding of p75NTR. The results of these studies will enable the introduction of two complimentary, non-invasive, and reiterative measures of small fibre damage and repair, thus enabling efficient, but accurate, assessment of treatment efficacy in human diabetic neuropathy.